Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutières Syndrome.

Abstract

Detection of intracellular DNA triggers activation of the stimulator of IFN genes-dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3' repair exonuclease that degrades cytosolic DNA, cause Aicardi-Goutières syndrome and chilblain lupus. Trex1 (-/-) mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1 (-/-) mice have not been defined. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS). In this study, we show that Trex1 (-/-) mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies. These findings implicate cGAS as a key driver of autoimmune disease and suggest that cGAS inhibitors may be useful therapeutics for Aicardi-Goutières syndrome and related autoimmune diseases.

• Authors: Elizabeth E Gray, Piper M Treuting, Joshua J Woodward, Daniel B Stetson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 5 Pg. 1939-43 (Sep 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26223655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Autoantibodies
• Nucleotides, Cyclic
• Phosphoproteins
• cyclic guanosine monophosphate-adenosine monophosphate
• Interferon-beta
• Interferons
• Nucleotidyltransferases
• cGAS protein, mouse
• Exodeoxyribonucleases
• three prime repair exonuclease 1

Topics

• Animals
• Autoantibodies (blood, immunology)
• Autoimmune Diseases of the Nervous System (genetics, immunology, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Embryo, Mammalian (cytology)
• Exodeoxyribonucleases (genetics, immunology, metabolism)
• Fibroblasts (drug effects, immunology, metabolism)
• Gene Expression (drug effects, immunology)
• Humans
• Immunoblotting
• Inflammation (genetics, immunology, metabolism)
• Interferon-beta (genetics, immunology, metabolism)
• Interferons (immunology, pharmacology)
• Macrophages (drug effects, immunology, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Nervous System Malformations (genetics, immunology, metabolism)
• Nucleotides, Cyclic (immunology, metabolism)
• Nucleotidyltransferases (genetics, immunology, metabolism)
• Phosphoproteins (genetics, immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction